Relationships Between Sulcal
Asymmetries and Corpus Callosum Size:
Gender and Handedness Effects
E. Luders1,2, D.E. Rex2, K.L. Narr2, R.P. Woods2, L. Jancke3,
P.M. Thompson2, J.C. Mazziotta2 and A.W. Toga2
Magnetic resonance imaging was used to establish the presence
and nature of relationships between sulcal asymmetries and midsagittal callosal size in neurologically intact subjects, and to
determine the influences of sex and handedness. Against a background of long-standing disputes, effects of gender and handedness
on callosal size, shape, and variability were additionally examined.
Both positive and negative correlations between sulcal asymmetry
and callosal size were observed, with effects influenced by sex and
handedness. The direction of relationships, however, were dependent on the regional asymmetry measured and on whether real or
absolute values were used to quantify sulcal asymmetries. Callosal
measurements showed no significant effects of sex or handedness,
although subtle differences in callosal shape were observed in
anterior and posterior regions between males and females and
surface variability was increased in males. Individual variations in
callosal size appear to outrange any detectable divergences in size
between groups. Relationships between sulcal asymmetries and
callosal size, however, are influenced by both sex and handedness.
Whether magnitudes of asymmetry are related to increases or
decreases in callosal size appears dependent on the chosen
indicators of asymmetry. It is an oversimplification, therefore, to
assume a single relationship exists between cerebral asymmetries
and callosal connections.
callosal size in right compared with left handers and ambidextrous individuals. Gender by handedness interactions, as
reported by Denenberg et al. (Denenberg et al., 1991) and Habib
et al. (Habib et al., 1991) also appear present where larger
callosal anterior midbody regions in right-handed females, lefthanded and non-consistent right-handed males as well as larger
posterior midbody regions in consistent right-handed females
have been documented. Several studies, however, have failed to
detect differences in callosal morphology in association with
hand preference (Kertesz et al., 1987; Steinmetz et al., 1992,
1995). A number of explanations may account for discrepancies
in results between laboratories including the composition of
brains examined, and differences in the methods employed for
measuring callosal subregions. The largest source of discrepancy,
however, is likely attributable to the failure of most prior studies
to take total brain weight or volume into account.
Cerebral lateralization, in addition to sex and handedness, may
also inf luence callosal morphology. For example, if pro- cessing
resources were shared between the hemispheres, this would
lead to increased requirements for hemispheric communication, and thus a positive correlation between functional
lateralization and callosal size may be observed. However, e.g.
Hines and colleagues (Hines et al., 1992) observed a negative
correlation between language lateralization and the size of the
callosal splenium. This finding lends support to the hypothesis
that when the processing takes place solely or dominantly in a
single hemisphere, there may be less need for interhemispheric
information exchange. This could be related to a decreased
callosal size, and therefore a negative correlation may exist
between functional lateralization and callosal size. In contrast,
others view callosal size as an indicator for hemispheric
isolation: the larger the CC, the greater the interhemispheric
inhibition, and the more isolated the hemispheres in function
(Clarke et al., 1993; Clarke and Zaidel, 1994; Hellige et al., 1998).
Additionally, Cook (Cook, 1984a,b,c) proposed a mech- anism
for interhemispheric communication in which the pattern of
cortical activation in one hemisphere results in ipsilateral
surround inhibition and contralateral homotopic inhibition.
Therefore, if the CC is assumed to have an inhibitory function,
and if we suppose a stronger inhibition in asymmetric brains, we
might expect to find positive relationships between CC size and
asymmetry measures.
Although functional lateralization has been hypothesized to
be linked with the degree of structural asymmetry (Foundas et
al., 1994, 1996; Jancke et al., 1994; Schlaug et al., 1995;
Steinmetz, 1996; Amunts et al., 1996, 2000), surprisingly few
human studies have examined the relationships between
structural asymmetries and callosal morphology directly. Based
on negative correlations revealed between the density of callosal
projections and volumetric asymmetry in the cortex of the rat,
Rosen and colleagues (Rosen et al., 1989, 1990) and Galaburda et
Introduction
Gender differences in callosal morphology have long been in
dispute. Sexual dimorphisms reported from post-mortem and
magnetic resonance imaging (MRI) studies include (i) larger total
or forebrain volume-adjusted size of the corpus callosum (CC)
in females (Holloway and DeLacoste, 1986; Johnson et al.,
1994; Steinmetz et al., 1995); (ii) larger raw (Witelson, 1989;
Steinmetz et al., 1992; Clarke and Zaidel, 1994) or proportional
isthmus areas in females (isthmus relative to total CC) (Witelson,
1989); (iii) larger raw or proportional splenial areas in females
(DeLacoste-Utamsing and Holloway, 1982; DeLacoste et al.,
1986; Holloway and DeLacoste, 1986; Clarke et al., 1989;
Davatzikos and Resnick, 1998); (iv) larger posterior callosal
regions in males (Denenberg et al., 1991), and (v) shape
differences indicating a more bulbous splenium in female
compared to male subjects (DeLacoste-Utamsing and Holloway,
1982; Holloway and DeLacoste, 1986; Clarke et al., 1989; Allen
et al., 1991). In addition, when comparing angles determined by
lines connecting particular points of the CC and other brain
regions, gender differences have been observed in the orientation of the CC (Oka et al., 1999). Although these findings
suggest that sexual dimorphisms exist in callosal morphology,
replications have not been consistent across laboratories, for a
review see Bishop and Wahlstein (Bishop and Wahlstein, 1997).
Results are similarly mixed concerning relationships between
callosal size and handedness. Post-mortem (Witelson, 1985,
1989; Witelson and Goldsmith, 1991) as well as in vivo studies
(Denenberg et al., 1991; Habib et al., 1991) have shown smaller
1
Institute of Experimental and General Psychology,
Otto-von-Guericke-University Magdeburg, Germany,
2
Laboratory of Neuro Imaging, Department of Neurology,
Center of Brain Mapping, UCLA School of Medicine, Los
Angeles, USA and 3Department of Neuropsychology, University
of Zurich, Switzerland
Cerebral Cortex Oct 2003;13:1084–1093; 1047–3211/03/$4.00
al. (Galaburda et al., 1990) have proposed that an inverse
relationship exists between the magnitude of anatomical
cerebral asymmetry and the extent of commissural connections
between the relevant cortical areas. Findings from some
investigations of the human brain further suggest that such an
inverse relationship exists. Specifically Aboitiz et al. (Aboitiz et
al., 1992b,c) and Zaidel et al. (Zaidel et al., 1995) analyzed
statistical associations between the degree of asymmetr y in
perisylvian regions [Sylvian fissure (SF) curved length, planum
temporale (PT) area and depth] and commissural connections
(indexed by the regional number of callosal fibers or by regional
callosal size) in post-mortem brains. In these investigations, a
negative correlation was obser ved between perisylvian asymmetries and the total numbers of fibers in the isthmus of males,
and in the anterior splenium of females (Aboitiz et al., 1992b).
Negative correlations between SF and PT asymmetries and the
size of the callosal isthmus were observed in males but not in
females (Aboitiz et al., 1992c) and between PT asymmetry and
the number of small diameter fibers in the isthmus of the CC,
again only in male brains (Zaidel et al., 1995). Only one study, to
our knowledge, has examined these relationships using in vivo
imaging data, where links between midsagittal callosal area and
overall cerebral asymmetry (measured from one matched sagittal
brain slice in each hemisphere) were assessed (Dorion et al.,
2000). Results showed a negative correlation between cerebral
asymmetry and total callosal size in male subjects. A lthough
methods differ considerably, all of these studies suggest a
sex-dependent decrease in callosal size and fiber number with
increasing cerebral asymmetr y. However, not all of these
investigations employed brain size corrections to control for
differences in the magnitude of asymmetry between genders.
Importantly, males are well known to possess larger brains and
are thus expected to exhibit larger hemispheric differences.
Furthermore, it is possible that post-mortem measurements may
be compromised by a non-uniform shrinkage of the CC. Finally,
measurements obtained from one brain slice in each hemisphere
may be a less precise index of asymmetry and sensitive to the
orientation of each brain volume.
In the present study, our first goal was to confirm the
presence, and establish the nature of relationships between
callosal size and well documented indices of sulcal asymmetries
(Thompson et al., 2000; Blanton et al., 2001; Narr et al., 2001;
Sowell et al., 2002a). Sulcal asymmetr y was defined as the
interhemispheric difference in the surface location of a defined
single point representing the anterior, posterior, superior or
inferior end of a sulcus. Points rather than linear measures
(although highly correlated) were used as asymmetry measures
as based on previous analyses showing that points from the
sulcal extremes are slightly better predictors of cerebral asymmetry than hemispheric differences in sulcal lengths or heights
(Narr et al., 2001). For example, measures of SF posterior
extrema are highly correlated with SF horizontal length, and
measures of SF superior extrema are highly correlated with
measures of SF height. Sulcal extreme points represent a proxy
to the positions and extent of the tissue, encompassed by
the respective sulci. For example, the posterior extent of the
superior temporal sulcus ascending branch represents
the angular gyrus. The termination of this sulcus is in the bend of
the angular gyrus. It represents a single point that is sufficiently
stable to serve as a proxy for the position of the angular gyrus.
Thus, hemispheric differences in the location of sulcal extrema
express the positional or size dependent asymmetr y of a
particular brain region. The degree of structural asymmetry has
been hypothesized to be linked with functional asymmetry,
while both structural and functional asymmetry are proposed to
be associated with the degree of interhemispheric
communication or callosal connectivity. However, given that
there is a disagreement in the existing literature concerning
whether increased callosal connectivity is associated with more
versus less lateralization and that existing empirical data are
relatively sparse, our hypotheses were two-tailed.
Asymmetr y measures included sulcal measurements from
frontal, temporal and parietal regions. Measures were specifically chosen from posterior brain regions established as
asymmetric in normal individuals and as important for language
processing. Finally, although less widely documented as asymmetric, we included sulcal measures surrounding anterior language regions from each hemisphere. Anatomical relationships
were investigated between sulcal asymmetries and total CC area
as well subareas of discrete callosal vertical partitions. To
our knowledge, it is the first 3-D in vivo study examining
associations between callosal sizes and cerebral asymmetry
using a refined set of sulcal extrema measures. Previous studies
have used only a single SF and PT asymmetry measurement or an
overall hemispheric asymmetry measure as based on a single
sagittal brain slice in each hemisphere.
As a second goal of this study we set out to examine whether
relationships between sulcal asymmetries and callosal size were
different in male and female subjects and between right- and
left-handed individuals, given that gender, handedness, and their
interactions appear to contribute to changes in callosal morphology. Furthermore, in light of above-mentioned controversies
concerning the inf luences of sex and handedness on callosal
morphology, we examined differences in callosal areas between
groups defined by biological sex and handedness in a large
and age-matched sample to help clarif y previous findings.
Anatomical surface based mesh modeling methods (Thompson
et al., 1996a,b, 1997; Narr et al., 2000, 2002) were further used
to characterize average shape and detailed surface variability
differences between groups.
Materials and Methods
Subjects
Subjects without any neurological, psychological or pathological impairment (n = 59) from the International Consortium for Brain Mapping
(ICBM) database of normal adults were included for study. Groups were
matched for biological sex, handedness and imaging site (McConnell
Brain Imaging Center at the Montreal Neurological Institute (MNI) of
McGill University, the Research Imaging Center (RIC) at the University of
Texas Health Science Center at San Antonio, and the Division of Brain
Mapping at the University of California, Los Angeles (UCLA) School of
Medicine). Handedness was quantified with a Laterality Quotient (LQ)
using the Edinburgh Handedness Inventory (EHI) (Oldfield, 1971). LQs
that approach –100 represent left-dominant subjects and those that
approach 100 represent right-dominant subjects. Only subjects with LQs
that represent largely left-dominance and largely right-dominance were
included (left handers mean LQ = 78.5, SD = 23.8; right handers mean
LQ = 98, SD = 6.1). Cross-dominance was minimized to eliminate a
potential confound in the study. UCLA’s ICBM database contained only
four qualified left-handed females accounting for one less female lefthanded subject from this site. Overall, there were 15 male right-handed
subjects (mean age = 23.3 years, SD = 3.9), 15 male left-handed subjects
(mean age = 25.3 years, SD = 6.2), 15 female right-handed subjects (mean
age = 23.3 years, SD = 3.9), and 14 female left-handed subjects (mean age
= 25.4 years, SD = 5.7). All subjects gave informed consent according to
institutional guidelines.
MRI Acquisition
T1-weighted spoiled grass (SPGR) whole brain MRI scans were obtained
for each subject (MNI: 1.5 T Siemens, 176 × 256 × 256 1 × 1 × 1 mm
Cerebral Cortex Oct 2003, V 13 N 10 1085
voxels; RIC: 2 T Elscint, 190 × 256 × 256 1 × 1 × 1 mm voxels; UCLA: 3 T
General Electric, 124 × 256 × 256 1.2 × 1 × 1 mm voxels).
Image Preprocessing
Sulcal Asymmetry Measures
To obtain sulcal asymmetry measures, image volumes passed through a
number of preprocessing steps. First, image volumes were corrected for
signal intensity inhomogeneities (Zijdenbos et al., 1994; Zijdenbos and
Dawant, 1994; Sled et al., 1998), and transformed into ICBM 305 stereotaxic space using an automatic nine-parameter linear transformation
(Woods et al., 1998). Using signal intensity information a spherical mesh
surface was created and continuously deformed to fit a threshold intensity
value which best differentiates extra-cortical cerebrospinal f luid from
underlying cortical gray matter (MacDonald et al., 1994). The resulting
3-D cortical surface models from each subject were used to manually
outline primary cortical surface sulci and fissures in each hemisphere by
two raters blind to group status (Thompson et al., 2000; Sowell et al.,
2002a,b). Images volumes in coronal, axial and sagittal planes were
available simultaneously to aid decisions when the brain anatomy
was ambiguous. Detailed anatomic protocols for delineating cortical
anatomy are available at http://w w w.loni.ucla.edu/NCRR/Protocols/
SulcalAnatomy.html and have been previously validated (Blanton et al.,
2001; Narr et al., 2001; Sowell et al., 2002a). The reliability for the sulcal
delineation procedure was established with an inter-rater error of <2 mm
for all sulci (right hemisphere only) of six different randomly selected
brains (Sowell et al., 2002a). A fter outlining the cortical surface sulci, we
identified the surface locations of defined points representing sulcal
openings and/or termination points from anterior, posterior, superior or
inferior sulcal extrema [minima or maxima in z (horizontal) or y (vertical)
dimensions]. Sulcal measures ref lect distances as measured from the
anterior commissure, which was defined as the origin in each brain
volume (0,0,0 in x,y,z coordinates).
For the present study, only sulcal parameters exhibiting highly
significant hemispheric asymmetries in posterior temporo-parietal
regions as identified in both normal and diseased populations (Narr et al.,
2001) were used to assess associations with vertically partitioned
Figure 1. Three-dimensional model of the cerebral cortex showing sulcal landmarks
and callosal area measures. Structures are visualized as follows: (1) splenium, (2)
isthmus, (3) posterior midbody, (4) anterior midbody, (5) anterior third, (a) posterior
extrema of the SF, (b) superior extrema of the SF, (c) SF inferior extrema of the anterior
horizontal ramus, (d) SF anterior extrema of the anterior vertical ramus, (e) sulcus
triangularis inferior extrema, (f) post central sulcus anterior extrema, and (g) posterior
extrema of the superior temporal sulcus ascending branch. Although the SF posterior
and superior extrema seem to represent the same extrema in Figure 1, the posterior
ending of the SF is represented by an extrema in the vertical dimension, while the
superior ending of the SF is represented by a different extrema in the horizontal
dimension.
1086 Corpus Callosum and Sulcal Asymmetries • Luders et al.
midsagittal areas of the CC. These measures were also chosen because
they delimit posterior brain regions established as important for language
processing. Measures included the posterior and superior extrema of
the SF, the anterior extrema of the post central sulcus and the posterior
extrema of the superior temporal sulcus ascending branch. Additionally,
we examined relationships between callosal areas and sulcal parameters
delimiting anterior language regions. These measures included the SF
inferior extrema of the anterior horizontal ramus, the SF anterior extrema
of the anterior vertical ramus and the sulcus triangularis inferior extrema
(Fig. 1).
Callosal Measures
One rater, blind to gender and handedness, delineated the CC in the
midsagittal sections of native brain volumes after correcting image
volumes for signal intensity inhomogeneities (Zijdenbos et al., 1994;
Zijdenbos and Dawant, 1994; Sled et al., 1998) using a 3-D visualization
program (Woods, 2001). Midsagittal brain sections were defined by
identifying the interhemispheric fissure in the coronal and sagittal planes
and confirmed by the presence of the falx cerebri. For inter-rater
reliability, the CC from six different randomly selected brains were
contoured by two independent investigators. The intraclass correlation
coefficient obtained for total CC area was r = 0.99. The midsagittal callosal
renderings in native space were reoriented to maximize callosal length
and divided into five vertical partitions representing the (i) splenium, (ii)
isthmus, (iii) posterior midbody, (iv) anterior midbody and (v) anterior
third (Fig. 2). This parcellation scheme was devised by Witelson
(Witelson, 1989) based on electron microscopic study of callosal fibers in
the macaque, and validated by Aboitz et al. (Aboitz et al., 1992a) in
post-mortem analyses as well as by Clarke and Zaidel et al. (Zaidel et al.,
1994) in in vivo analyses.
Midsagittal area measures were acquired in mm2 for each segment as
well as for the entire CC. In order to clarify findings concerning gender
specific shape differences of splenial area (DeLacoste-Utamsing and
Holloway, 1982; Holloway and DeLacoste, 1986; Clarke et al., 1989;
Allen et al., 1991), the splenial extent in the y-dimension (length) was
measured in mm.
Finally, to obtain maps of average callosal anatomy and detailed
surface variability information, callosal surfaces were delineated in ICBM
305 stereotaxic space as detailed above, and surface-based anatomical
Figure 2. Delineation and partitioning of the midsagittal corpus callosum in
T1-weighted MR images. The CC was traced in the most medial brain slices. The
partitioning scheme adapted from Witelson (Witelson, 1989), Aboitiz and colleagues
(Aboitiz et al., 1992a), and Clarke and Zaidel (Clarke and Zaidel, 1994) was employed to
divide callosal areas into the splenium, representing the posterior fifth of callosal area,
the isthmus representing two-fifteenths, the posterior midbody and anterior midbody,
both representing one-sixth of callosal area; and the anterior third as shown.
mesh modeling methods were applied (Thompson et al., 1996a,b, 1997).
For these procedures surface points making up each callosal outline were
made spatially uniform in 3-D. Homologous callosal surface points were
then matched between subjects within groups defined by biological sex
and/or handedness in all three dimensions. The mean and root mean
square distance between these sets of points were calculated to provide
maps of average callosal shape and variability on a point-by-point basis
across the entire surface in standard ICBM 305 space.
Brain Volume
Brain volume was estimated from the cortical surface models described
above in raw scanner space. That is, the 3-D cortical surface models were
mapped back onto each image volume and masks of brain tissue were
obtained. Any small errors in the masks were corrected manually. All
extra-cerebral tissue was then removed from the image volumes based on
the brain mask to provide measures of intracranial brain volume that
included all tissue types (gray matter, white matter, and cerebrospinal
f luid) but that excluded the cerebellum.
Statistical Analysis
Corpus Callosum Morphology and the Inf luence of Gender and
Handedness
In order to control for the inf luence of total brain volume on midsagittal
callosal (sub)areas and splenial length, the CC measures obtained in raw
scanner space were residualized by the square of the cubed root (area
measures) or by the cubed root (length) of each individual brain volume.
For comparisons between groups defined by biological sex and handedness we used multivariate analyses of variance, which were followed by
univariate analyses when appropriate. Morphometric variables were used
as repeated measures in a two (Gender) by two (Handedness) design and
included the residualized areas of (i) the total callosum, (ii) the anterior
third, (iii) the anterior midbody, (iv) the posterior midbody, (v) the
isthmus, (vi) the splenium and (vii) the splenial length as dependent
measures. Although the primary objective of this study was to examine
differences in callosal size after controlling for individual differences in
brain volume, we also performed analyses without taking brain volume
into account in order to compare our findings with others in the literature. Using Bonferroni corrections for these tests was considered overly
conservative given that MANOVAs already protect against inf lated Type I
error (Tabachnick and Fidel, 1996). Finally, differences in total brain
volume between groups defined by sex and handedness were examined
using standard analyses of variance.
Relationships Between Sulcal Asymmetry and Callosal Area Measures
The term ‘sulcal asymmetry’ refers to the interhemispheric difference of
the location of defined points representing sulcal extrema. Asymmetry
coefficients for sulcal extrema were calculated by subtracting right from
left hemisphere sulcal measures (L–R). As described previously, sulcal
measures were obtained after brain volumes had been transformed into
average 305 stereotaxic space, thus already controlling for brain size
contributions to increases in cortical asymmetry indices as may occur
between genders. Given that brain size differences for sulcal parameters
were controlled, it was therefore unnecessary to divide asymmetr y
measures by the sum of left and right hemispheric values to obtain relative
asymmetr y measures. Pearson’s correlation coefficients were used to
establish linkages between residual callosal areas and sulcal asymmetry
measures.
In previous studies, both absolute and directional asymmetry
measures have been used to examine relationships between hemispheric
asymmetries and callosal size. To establish which of these approaches
was more appropriate, we calculated the exact probability that
distributions for asymmetry coefficients from each sulcal measure could
have arisen by chance by modeling the data as a binomial distribution
using equal probabilities that right or left measures were more extreme.
For measures revealing significant deviations (P ≤ 0.01) from this
directionally unbiased binomial distribution, that is when measures
indicated a significant leftward or rightward shift in sulcal asymmetry,
we used real values (positive and negative) to examine if leftward or
rightward asymmetries inf luence the direction of the correlations with
callosal areas. For measures indicating no significant sulcal asymmetry
shift in either direction, absolute values were used for correlations
between callosal areas and asymmetr y. The results of these tests are
presented in the Results section.
To determine the appropriate Bonferroni correction for having
performing multiple correlations between sulcal asymmetry measures
and callosal area measurements, we examined the relationships between
different sulcal asymmetry indices (separately for absolute value and real
value asymmetry indices as established above). Measures that were highly
correlated were counted as a single measure for the purpose of Bonferroni
correction. Correlations between the dependent measures are provided
in the Results section. Significance was determined with a two-tailed
probability value of alpha less than 0.05.
Results
Corpus Callosum Morphology and the Inf luence of
Gender and Handedness
Table 1 shows means and standard deviations for total brain
volume and callosal measures obtained in raw scanner space for
the overall sample and for groups defined by biological sex and
handedness.
Total brain volumes obtained from the present sample of
young adults are somewhat smaller in comparison to other postmortem and in vivo measures as found in the literature given
that the cerebellum was excluded when estimating the brain
volume. As expected, males possessed significantly larger brain
volumes compared with females (P ≤ 0.001; F = 29.34). Callosal
(sub)regions revealed no significant differences between males
and females both before and after brain size correction. Size and
shape differences of callosal surface anatomy may be visualized
between males and females in Figure 3 where surface averages
are superimposed from each group in standard 305 stereotaxic
space. As illustrated, differences between males and females
appear situated predominantly in anterior and posterior callosal
regions, and a subtle shape difference can be identified in the
splenial region (although the gender difference of the splenial
Table 1
Means (and SD) of brain volume and areas of the corpus callosum
Brain volume (l)
Total CC (mm2)
Anterior third (mm2)
Anterior midbody (mm2)
Posterior midbody (mm2)
Isthmus (mm2)
Splenium (mm2)
Splenium Length (mm)
Total n
Male
Female
Left-handed
Right-handed
1.12 (0.13)
654.54 (86.92)
251.89 (40.78)
77.75 (12.45)
70.68 (11.51)
59.01 (12.33)
190.04 (28.68)
18.79 (2.50)
1.19 (0.12)
676.96 (93.77)
261.34 (43.60)
78.75 (14.48)
71.63 (10.86)
62.34 (13.06)
197.60 (31.54)
19.92 (2.71)
1.05 (0.10)
631.34 (73.82)
242.12 (35.80)
76.71 (10.09)
69.70 (12.26)
55.57 (10.67)
182.21 (23.43)
17.62 (1.60)
1.12 (0.13)
653.45 (95.32)
249.98 (43.94)
77.70 (13.71)
70.57 (13.44)
60.94 (11.31)
189.20 (28.66)
18.90 (2.34)
1.12 (0.12)
655.58 (79.60)
253.74 (38.15)
77.79 (11.34)
70.79 (9.52)
57.14 (13.15)
190.85 (29.17)
18.69 (2.68)
Cerebral Cortex Oct 2003, V 13 N 10 1087
Figure 3. Callosal surface averages mapped in groups defined by sex and handedness.
The average parametric midsagittal mesh models of the CC in the average ICBM 305
stereotaxic space are shown in different colors to illustrate differences between groups
with females (n = 29) shown in red, males (n = 30) in blue, right-handed subjects
(n = 30) in green, and left-handed subjects (n = 29) in pink. The anterior third is on the
left and the splenium on the right.
length was not identified as significant in the omnibus analysis
described above).
Total brain volume and callosal regions did not differ
significantly between left- and right-handed subjects before and
after brain size correction. Furthermore, no significant interactions between gender and handedness were observed for any
of these measures. Superimposed surface maps of the CC
averaged within right and left handers in 305 space are
consistent with statistical analyses where surface averages are
almost perfectly aligned, although small differences may exist in
splenial regions (Fig. 3).
Corpus Callosum Surface Variability
The surface variability of the CC, shown in Figure 4, appears
larger in males than in females for the overall sample and in
groups defined by hand preference and sex. In contrast, similar
variabilities exist in the CC when groups are divided by hand
preference only. In callosal subregions, higher variabilities are
seen in all groups in the anterior and posterior borders of the
splenium and the anterior third of the CC. The smallest
inter-individual differences in females are present in the inferior
and superior borders of the isthmus and the posterior midbody
as well as in the inferior surface of the CC anterior third. The
least variability in males, left handers and right handers can be
seen in the inferior surface of the CC anterior third.
Relationships Between Sulcal Asymmetry and Callosal
Area Measures
Results from exact binomial modeling revealed significant
(P ≤ 0.01) leftward or rightward asymmetries for the following
1088 Corpus Callosum and Sulcal Asymmetries • Luders et al.
Figure 4. Callosal surface variability mapped separately in groups defined by sex and
handedness. Presented are the (a) overall female sample (n = 29), (b) overall male
sample (n = 30), (c) left-handed females (n = 14), (d) left-handed males (n = 15), (e)
right-handed females (n = 15), (f) right-handed males (n = 15), (g) overall left-handed
sample (n = 29), (h) overall right-handed sample (n = 30). The color bar encodes the
root mean square magnitude (in millimeters) of the displacement vectors required to
map equivalent surface points from each individual to the group average. The anterior
third is on the left and the splenium on the right.
Table 2
Correlations of real value asymmetry indices
STS
PSA
SFP
STS
PSA
SFP
1.000
0.406**
0.488**
–
1.000
0.526**
–
–
1.000
**Significant correlations with a two-tailed probability value of 0.01 (STS = superior temporal
sulcus ascending branch posterior extrema, PSA = post central sulcus anterior extrema, SFP =
Sylvian fissure posterior extrema).
sulcal measures: (i) the superior temporal sulcus ascending
branch posterior extrema, (ii) post central sulcus anterior
extrema, and (iii) SF posterior extrema. Relationships between
the real values of these hemispheric asymmetry measures and
callosal areas were thus assessed. All of these variables were
significantly correlated (Table 2), and therefore considered as a
single hypothesis test. Corrections for multiple comparisons
were thus not applied.
Statistical tests assessing the relationships between callosal
areas and these sulcal asymmetry measures revealed that when
the asymmetr y was biased, increased asymmetries predicted
Table 3
Summary of significant correlations between real value sulcal asymmetry coefficients and callosal
areas
Region
Total n
(n = 59)
Males
(n = 30)
Sylvian fissure posterior extrema (SFP)
Total area
–0.288*,a
–
Anterior third
–0.314*,a
–
Post central sulcus anterior extrema (PSA)
Splenium
–
0.361*,b
Females
(n = 29)
Left-handed
(n = 29)
Right-handed
(n = 30)
–
–
–
–0.399*,a
–0.444*,a
0.370*,b
–
–
*Significant correlations with a two-tailed probability value of 0.05.
Table 4
Correlations of absolute value asymmetry indices
SFS
SFI
STI
SFA
SFS
SFI
STI
SFA
1.000
–0.305*
–0.402**
0.049
–
1.000
0.650**
–0.308*
–
–
1.000
–0.072
–
–
–
1.000
*Significant correlations with a two-tailed probability value of 0.05
**Significant correlations with a two-tailed probability value of 0.01 (SFS = Sylvian fissure
superior extrema, SFI = Sylvian fissure inferior extrema of the anterior horizontal ramus, STI =
sulcus triangularis inferior extrema, SFA = Sylvian fissure anterior extrema of the anterior vertical
ramus).
a
Negative r-values reflect associations between increased callosal areas and increased leftward
asymmetries.
b
Positive r-values reflect associations between increased callosal areas and decreased leftward
asymmetries.
Table 5
Summary of significant correlations between absolute value sulcal asymmetry coefficients and
callosal areas
Region
Total n
(n = 59)
Males
(n = 30)
Females
(n = 29)
Left-handed
(n = 29)
Sulcus triangularis inferior extrema (STI)
Splenium
–
–
–
–0.386*
Sylvian fissure inferior extrema of the anterior horizontal ramus (SFI)
Anterior midbody–
–
0.441*
–
Sylvian fissure superior extrema (SFS)
Anterior midbody–
–
–
–
Isthmus
–
–0.375*
–
–
Splenium
–
–
0.368*
–
Right-handed
(n = 30)
–
–
0.413*
–
–
*Significant correlations with a two-tailed probability value of 0.05.
Figure 5. Relationships between real and absolute sulcal asymmetry measures and
callosal size. Examples of correlations between absolute (a, b) and real (c, d) values of
sulcal asymmetries (plotted on the x-axes in mm) and callosal regions (plotted on the
y-axes in mm2). (a) Relationships between splenium and sulcus triangularis inferior
extrema (STI) in left handers (LH). (b) Relationships between anterior midbody and
Sylvian fissure inferior extrema of the anterior horizontal ramus (SFI) in females. (c)
Relationships between anterior third and Sylvian fissure posterior extrema (SFP) in right
handers (RH). (d) Relationships between splenium and post central sulcus anterior
extrema (PSA) in males. The solid line marks the significant correlation, the dotted line
the non-significant correlation.
larger areas of the midsagittal CC. These relationships were
significant for the SF posterior extrema and total callosal area,
and for the SF posterior extrema and the CC anterior third (for
the whole sample and in right handers). The inverse relationship, however, also appeared true for some highly asymmetric
sulcal measures. That is, greater asymmetry bias and decreases in
CC areas were revealed for the post central sulcus anterior
extrema and the splenium in males and in left handers (Table 3,
Fig. 5).
Measures indicating no significant sulcal asymmetry shift in
any direction from exact binomial modeling were found for the
(i) SF superior extrema, (ii) sulcus triangularis inferior extrema,
(iii) SF anterior extrema of the anterior vertical ramus and (iv) SF
inferior extrema of the anterior horizontal ramus. For these
sulcal measures relationships between the absolute values of
hemispheric asymmetry and callosal areas were assessed. Again,
Bonferroni corrections were not employed for these sulcal
asymmetry measures given that all asymmetry indices were significantly correlated (Table 4).
In males, a significant negative correlation between SF
superior extrema asymmetry and callosal isthmus was obser ved.
There was also a significant negative correlation between the
asymmetr y of the sulcus triangularis inferior extrema and
splenium in left handers. In contrast, a positive correlation was
found between the asymmetry index of the SF inferior extrema
of the anterior horizontal ramus and the anterior midbody in
females. Additionally, we obser ved positive correlations between SF superior extrema asymmetry and anterior midbody in
right handers, and splenium in females (Table 5).
Discussion
Gender Effects on Corpus Callosum Morphology
Significant differences were not obser ved in comparisons of
callosal areas between groups defined by biological sex. These
results are consistent with a number of studies that have failed to
replicate some early findings of gender specific differences in
callosal morphology. As argued by Bishop and Wahlstein (Bishop
and Wahlstein, 1997) based on their review of 49 independent
studies on the human CC from 1982 to 1994, there is insufficient
evidence to support the presence of sex-related differences in
the size or shape of the splenium, whether or not adjustments
are made for overall brain size. Similarly, our results suggest that
the effect of individual variation in callosal size is large enough to
outrange any effect of callosal size differences between males
and females.
The gender-specific maps of callosal surface anatomy (Fig. 3)
demonstrate, however, after correcting for brain size by transforming image volumes into average stereotaxic 305 space, that
Cerebral Cortex Oct 2003, V 13 N 10 1089
small differences between male and female CC are present and
are predominantly situated in anterior and posterior callosal
regions. These differences might be the result of a somewhat
longer CC in females, although this hypothesis was not examined
empirically. Maps of callosal surface anatomy may also suggest a
slightly more bulbous splenial region in females that might agree
with the reported, although controversial, sexual dimorphism of
a more bulbous splenium in females (DeLacoste-Utamsing and
Holloway, 1982; Holloway and DeLacoste, 1986; Clarke et
al., 1989; Allen et al., 1991). This difference, however, was not
determined as significant in our analysis of splenial length
between groups defined by biological sex.
Handedness Effects on Corpus Callosum Morphology
Statistical analyses comparing individuals based on hand preference did not yield any significant differences for all callosal
measures before or after brain size correction. These results are
in contrast to some post-mortem findings by Witelson (Witelson,
1985, 1989) demonstrating that the CC of non-consistent
right-handed males tend to be thicker than those of consistent
right-handed males. A more recent study replicated these
findings (Witelson and Goldsmith, 1991) and results from some
in vivo investigations add further support to these findings
(Denenberg et al., 1991; Habib et al., 1991). Notwithstanding, in
line with our results, several other MRI studies have failed to
detect differences in callosal morphology in relation to
handedness (Kertesz et al., 1987; Steinmetz et al., 1992, 1995).
Maps of average callosal surface anatomy in right and left
handers (Fig. 3) suggest that diversity exists in the shape of the
splenium, but differences were not observed statistically. Nevertheless, given that splenial shape differences have also been
implicated previously between males and females, a more
refined measure of splenial shape (in addition to splenial length)
may be necessary to finally resolve the presence of both gender
and handedness differences in splenial morphology.
Sulcal Asymmetries and Callosal Size
Our study demonstrates that both positive and negative
associations exist between sulcal asymmetries in the human
brain and callosal area measures. As demonstrated by Aboitiz et
al. (Aboitiz et al., 1992a), an increased callosal area indicates an
increase in the total number of fibers crossing the CC. Therefore,
our findings support the hypothesis that increased asymmetry is
associated with increased callosal connectivity, but also support
the inverse relationship showing increased asymmetr y is
associated with decreased callosal connectivity. Importantly, the
direction of these relationships appear inf luenced by the
respective local indicators of cerebral asymmetry suggesting that
callosal fibers, whether through their primary or secondary
connections with different cortical regions, subser ve different
functions. These findings further suggest that relationships
between cerebral asymmetry and callosal size are local in nature.
The region-specific direction of associations between cerebral
asymmetry and callosal size seems to be plausible given that the
degree of structural asymmetry has been hypothesized to be
linked with the degree of functional lateralization, and given that
different brain functions subserved by different brain regions
are processed through different callosal channels and in
different ways (e.g. the non-dominant processing hemisphere
might or might not receive information from the dominant
processing hemisphere). Our data therefore show that it is an
oversimplification to assume a general (inversed) relationship
between cerebral asymmetry and callosal connectivity.
Previous anatomic studies support that different cortical
1090 Corpus Callosum and Sulcal Asymmetries • Luders et al.
regions project through specific callosal channels (DeLacoste et
al., 1985). Interestingly, in addition to significant correlations
supporting the assumption that cortical areas are topographically mapped in the CC, we also obser ved correlations
between posterior callosal regions and anterior cortical asymmetries (e.g. between callosal splenium and sulcus triangularis
inferior extrema) and, vice versa, between anterior callosal
regions and posterior cortical asymmetries (e.g. between callosal
anterior third and SF posterior extrema). Although these findings are not immediately understandable, they might lead to the
assumption that the nature of callosal pathways is probably
much more complex than pictured in present models of interhemispheric communication. Existing findings have already
suggested that callosal connectivity is more complex than
initially assumed. For example, it has been documented, that
primar y and secondar y somatosensory, auditory, and visual
information is transmitted via large diameter callosal fibers,
while higher-order sensory and cognitive information is transmitted through small diameter fibers (Aboitiz et al., 1992a).
A lthough connections across the corpus callosum have been
shown to be topographically organized where the relay of
sensory, motor and cognitive information are transmitted from
largely homologous regions in the two cerebral hemispheres,
there are differential representations of large and small diameter
fibers in different callosal channels (Aboitiz et al., 1992a).
Anterior callosal regions (connecting frontal brain regions) may
be more involved in the transmission of cognitive information,
and some middle and posterior connections appear more
involved in transmitting sensor y information (Clarke et al.,
1998). The isthmus, however, has been demonstrated to connect
myelinated fibers from posterior language regions and auditory
association areas, and has shown links with the performance
for the interhemispheric transfer of auditory stimuli as well as
semantic–verbal information that may also ref lect processing
capabilities in anterior language regions (Clarke and Zaidel,
1994).
The present results further demonstrate that the direction of
the correlations between sulcal asymmetry and callosal
measurements are sensitive to variations in the methods (e.g.
whether real or absolute asymmetry values are examined, or
whether brain size corrections are employed). Finally, individual
differences including sex and handedness are shown to be
important when determining the direction, magnitude and
significance of correlations between sulcal asymmetry measures
and midsagittal callosal size.
Negative Relationships and Absolute Asymmetry Measures
Negative correlations suggest that increased asymmetries in
frontal and temporo-parietal regions are associated with
decreased callosal size. In our study, negative relationships
between the absolute asymmetry values of sulcus triangularis
inferior extrema and the splenium in left handers, as well as
between SF superior extrema and isthmus in males were
demonstrated. These results agree with the in vivo findings of
Dorion et al. (Dorion et al., 2000), the post-mortem-results of
Aboitiz et al. (Aboitiz et al., 1992b,c) and Zaidel et al. (Zaidel et
al., 1995) in the human brain, as well as with the findings of
Rosen et al. examining asymmetries in rat cortices (Rosen et al.,
1989, 1990).
A number of additional post-mortem (Witelson, 1985, 1989;
Witelson and Goldsmith, 1991) and in vivo studies (Denenberg
et al., 1991; Habib et al., 1991, Hines et al., 1992) assessing
relationships between callosal size and hand preference also
suggest that right-handed individuals, who are presumably more
lateralized, have smaller callosal size than non-consistent
right-handed individuals. If we agree with the hypothesis that
anatomical asymmetr y is the substrate of the functional
lateralization and callosal size ref lects callosal connectivity, these
findings suggest, that increased hemispheric asymmetry occurs
with decreased callosal connectivity as already proposed by
Rosen et al. (Rosen et al., 1989, 1990) and Galaburda et al.
(Galaburda et al., 1990). This assumption is consistent with the
findings of negative correlations between sulcal asymmetry
measures and CC areas obser ved in our study as mentioned
above. Negative correlations between callosal size and cerebral
asymmetr y might be due to a decreased interhemispheric
information exchange with increasing cerebral asymmetr y.
Based on the assumption that the degree of structural asymmetry
is related to the degree of functional lateralization, increased
hemispheric independence/dominance may result in less interhemispheric communication.
Positive Relationships and Absolute Asymmetry Measures
Importantly, in addition to findings supporting inverse relationships between the magnitude of sulcal asymmetry measures and
callosal size, we found evidence to support that the opposite
relationship also applies for some sulcal asymmetry measures.
Positive correlations were obser ved between absolute asymmetry values of the SF inferior extrema of the anterior horizontal
ramus and the anterior midbody in female subjects, and between
SF superior extrema and anterior midbody in right handers, and
the splenium in females (Table 5). These findings might suggest,
in contrast to some previous reports, that increases in the
magnitude of cerebral asymmetries are associated with more,
rather than less callosal connectivity. Positive correlations
between callosal size and cerebral asymmetry might be due to an
increased need of interhemispheric communication with increasing cerebral asymmetry in order to relay results from the
dominant processing hemisphere to the non-dominant hemisphere. On the other hand, it might also be assumed, that an
increase in callosal size is related to an increase of interhemispheric inhibition. Thus, positive correlations between
callosal size and cerebral asymmetry may arise from a decreased interhemispheric information exchange with increasing
asymmetry. This assumption agrees with former theories understanding callosal size as an indicator for hemispheric isolation
(Clarke et al., 1993; Clarke and Zaidel, 1994; Hellige et al.,
1998), or indicative for ‘homotopic inhibition’ as described by
Cook (1984a,b,c).
Real Asymmetry Measures
Results revealed that if the asymmetry of the SF posterior
extrema is shifted leftward (typical shift), then the brains
showing the greatest shift exhibit larger overall areas of the CC
and of the CC anterior third. In contrast, brains with the most
extreme asymmetry of the post central sulcus anterior extrema
in the typical shifted direction (leftward), tend to have the
smallest spleniums. Therefore these results suggest that the
direction of cerebral asymmetries (typical vs atypical) inf luences the relationships between sulcal asymmetries and callosal
size.
Effects of Sex and Handedness on Relationships Between
Sulcal Asymmetries and Callosal Size
In this study, a positive relationship between the asymmetr y
index of the SF inferior extrema of the anterior horizontal ramus
and the CC anterior midbody, and between SF superior extrema
and splenium was observed in females. In contrast, a significant
negative relationship was obser ved between the post central
sulcus anterior extrema and the splenium in males if the
asymmetry was biased in the typical direction (leftward). In
addition, we found a significant negative correlation between
the asymmetry index of the SF superior extrema and isthmus in
males. The latter finding agrees with those of Aboitiz et al.
(Aboitiz et al., 1992b,c) and Zaidel et al. (Zaidel et al., 1995).
Using post-mortem brains, investigators obser ved a negative
correlation between perisylvian asymmetries and isthmal area or
the total numbers of fibers in the isthmus, in males. Our findings
together with those of Dorion et al. (Dorion et al., 2000), Aboitiz
et al. (Aboitiz et al., 1992b,c) and Zaidel (Zaidel, 1995) support
that sexually dimorphic processes in the brain might inf luence
the relationships between cerebral asymmetries and callosal
connectivity (Zaidel et al., 1995; Wisniewski, 1998). Nevertheless, it may be too speculative to relate our results in detail to
interpretations of gender-specific brain organization with regard
to our findings of different correlations between sulcal and
callosal measures in men and women. However, several studies
have documented that male brains may be more lateralized in
function (Shay witz et al., 1995; Hiscock et al., 2001) or
asymmetric in structure (Jancke et al., 1994; Kulynych et al.,
1994; Amunts et al., 2000) than female brains. Furthermore, on
average, men appear to possess better spatial and mathematical
abilities while women posses better verbal abilities (Kimura,
1999). Sex dependent relationships with respect to the SF
inferior extrema, which borders anterior language regions
(Broca’s), and the anterior midbody of the corpus callosum,
connecting primarily frontal brain regions, may thus ref lect
differences in the requirements for interhemispheric communication between males and females. It is possible that
females, if less functionally asymmetric, may rely on increased
interhemispheric communication and thus exhibit stronger
relationships between structural asymmetries and callosal size
in anterior callosal regions transmitting language related information.
Our finding of correlations in female subjects, results not
observed previously, might ref lect differences in methods with
regard to including brain size corrections. Brain size contributes
to increases in cortical asymmetry, where the magnitudes of
left–right differences are greater in larger brains. Differences in
brain size between males and females may therefore have
implications for gender differences in cerebral asymmetries.
Similarly, relationships exist between callosal size and brain size
(Rauch and Jinkins, 1994; Jancke et al., 1997). Brain size
corrections are therefore clearly necessary to accurately establish the direction and magnitude of relationships between
structural asymmetr y measures and CC size. In addition,
relationships between cerebral asymmetries and callosal
variables appear dependent on the asymmetry measures used for
assessment (area, volume, sulcal extreme, slope, length, height,
etc.). This assumption may partially explain why previous
studies found only negative relationships between callosal size
and hemispheric asymmetr y measures while we found both
positive and negative relationships to exist when using seven
different sulcal asymmetry measures from brain regions
established as important for language processing. Other possible
explanations for discrepancies in results regarding the direction
of these relationships may be attributable to measuring fiber
density as oppose to callosal area. As visualized in Figure 5, an
additional gain of information is revealed by using real left
minus right asymmetry measures in contrast to absolute value
asymmetry indices, as statements regarding whether leftward or
Cerebral Cortex Oct 2003, V 13 N 10 1091
rightward asymmetry has an inf luence on the direction of the
correlation may be interpreted.
Hand preference in addition to biological sex appeared to
inf luence the direction and magnitude of relationships between
sulcal asymmetry measures and callosal areas. Positive relationships between the SF superior extrema and anterior midbody in
right handers were exhibited, as well as between the SF
posterior extrema, total callosal area, and the CC anterior third in
right handers if the asymmetry was biased in the typical direction (leftward). In contrast, we observed a negative correlation
between the sulcus triangularis inferior extrema and splenium in
left handers. An additional negative relationship was detected
between the post central sulcus anterior extrema and the
splenium in left handers if the asymmetr y was biased in
the typical direction (leftward). Significant associations between
asymmetr y measures and anterior callosal regions (anterior
midbody, anterior third) were therefore more prominent in right
handers while significant correlations with posterior callosal
regions (splenium) were apparent in left handers. These results
may suggest a dimorphic organization in the brains of left and
right handers inf luencing regionally specific relationships
between surface asymmetries and callosal connectivity.
Notes
This work was supported by Deutsche Forschungsgemeinschaft (DFG) JA
737/8-1, National Library of Medicine Grant LM/M H05639, NCRR Grant
RR05056, and National Institute of Neurological Disorders and Stroke
(NINDS) Grant NS38253, Human Brain Project Grant to the International
Consortium for Brain Mapping (P20-MHDA52176), funded by National
Institute of Mental Health (NIMH), National Institute on Drug Abuse,
National Cancer Institute, and NINDS Grant P20 MH/DA52176, by P41
Resource Grant RR13642 from the NCRR. For generous support, the
authors also wish to thank the Brain Mapping Medical Research
Organization, the Pierson-Lovelace Foundation, the A hmanson Foundation, the Tampkin Foundation, the Jennifer Jones Simon Foundation, and
the Robson Family.
Address correspondence to Dr Arthur W. Toga, Laboratory of Neuro
Imaging, Department of Neurology, UCLA School of Medicine, 710
Westwood Plaza, 4238 Reed, Los Angeles, CA 90095-1769, USA. Email:
toga@loni. ucla.edu.
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